The long-term goal of the proposed work is to provide evidence that changes in iron homeostasis relate to the development and progression of atherosclerosis. Atherosclerosis or plaque buildup in arteries is the disease responsible for the vast majority of heart attacks, strokes, and events due to peripheral vascular disease that together cause death and disability for tens of millions of Americans. A relatively unexplored hypothesis explaining why women have a 10-20 year lag in onset of cardiovascular events due to atherosclerosis (CVD) is that monthly loss of iron is cardioprotective, and that cessation of menses at menopause accelerates CVD. Preventive approaches based on hormone therapy have been disappointing, causing increases in stroke and cardiovascular events instead of reductions. Additional motivation to investigate iron in CVD arises from recent evidence identifying the effects of inflammation and iron on hepcidin, the key regulator of macrophage iron uptake and release. Furthermore, iron catalyzes the generation of free radicals that oxidize cholesterol stimulating atheroma formation. Magnetic resonance imaging (MRI) is ideally suited to study iron because of iron's local effects on magnetic susceptibility that can be quantified using a relaxation parameter called T2* (`T2-star'), as well as the ability to noninvasively characterize and quantify atherosclerotic plaque with MRI. Thus, we seek in this work to provide critical evidence to motivate the development of novel diagnostics and therapeutics based on iron's role in atherosclerosis by achieving the following Specific Aims: Aim 1: Measure changes in arterial wall magnetic susceptibility in perimenopausal women. Hypothesis 1a: Arterial wall T2* decreases in the transition from perimenopausal to postmenopausal status. Hypothesis 1b: Carotid artery wall T2* varies inversely with wall thickness and pulse wave velocity. Aim 2: Identify changes in iron uptake mechanisms in perimenopausal women. Hypothesis 2: Serum hepcidin increases in the transition from perimenopausal to postmenopausal status. Aim 3: Identify differences in iron homeostasis that can influence plaque magnetic susceptibility. Hypothesis 3a: In vivo carotid plaque T2* varies inversely with intraplaque ferritin content. Hypothesis 3b: Patients with symptom-producing carotid artery plaque undergoing surgery have higher serum hepcidin levels compared to asymptomatic patients with carotid artery plaque undergoing surgery. Aim 4: Identify mechanisms relating plaque biomarkers and iron homeostasis to plaque progression in patients with carotid artery atherosclerosis. Hypothesis 4: Change in T2* has a negative association with plaque progression in asymptomatic patients with carotid artery atherosclerosis not requiring surgery. Significance: If vascular iron is shown to increase in women post-menopause and in atherosclerosis progression, we will have identified a truly novel target to attenuate CVD risk in both men and women. PUBLIC HEALTH RELEVANCE: Plaque buildup in arteries (atherosclerosis) causes heart attacks, strokes, and other complications that make heart and vascular disease the leading killer of Americans. Women tend to develop plaque buildup 10 to 20 years later than men. This research tests the theory that monthly loss of iron through menses is protective against atherosclerosis, which could lead to an entirely new approach to preventing and treating heart and vascular disease in both men and women.